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http://purl.uniprot.org/citations/24671090http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/24671090http://www.w3.org/2000/01/rdf-schema#comment"

Background

Mutations in the CEP290 (cilia-centrosomal protein 290 kDa) gene in Leber congenital amaurosis (LCA) cause early onset visual loss but retained cone photoreceptors in the fovea, which is the potential therapeutic target. A cone-only mouse model carrying a Cep290 gene mutation, rd16;Nrl-/-, was engineered to mimic the human disease. In the current study, we determined the natural history of retinal structure and function in this murine model to permit design of pre-clinical proof-of-concept studies and allow progress to be made toward human therapy. Analyses of retinal structure and visual function in CEP290-LCA patients were also performed for comparison with the results in the model.

Methods

Rd16;Nrl-/-mice were studied in the first 90 days of life with optical coherence tomography (OCT), electroretinography (ERG), retinal histopathology and immunocytochemistry. Structure and function data from a cohort of patients with CEP290-LCA (n = 15; ages 7-48) were compared with those of the model.

Results

CEP290-LCA patients retain a central island of photoreceptors with normal thickness at the fovea (despite severe visual loss); the extent of this island declined slowly with age. The rd16;Nrl-/-model also showed a relatively slow photoreceptor layer decline in thickness with ∼80% remaining at 3 months. The number of pseudorosettes also became reduced. By comparison to single mutant Nrl-/- mice, UV- and M-cone ERGs of rd16;Nrl-/-were at least 1 log unit reduced at 1 month of age and declined further over the 3 months of monitoring. Expression of GNAT2 and S-opsin also decreased with age.

Conclusions

The natural history of early loss of photoreceptor function with retained cone cell nuclei is common to both CEP290-LCA patients and the rd16;Nrl-/-murine model. Pre-clinical proof-of-concept studies for uniocular therapies would seem most appropriate to begin with intervention at P35-40 and re-study after one month by assaying interocular difference in the UV-cone ERG."xsd:string
http://purl.uniprot.org/citations/24671090http://purl.org/dc/terms/identifier"doi:10.1371/journal.pone.0092928"xsd:string
http://purl.uniprot.org/citations/24671090http://purl.uniprot.org/core/author"Stone E.M."xsd:string
http://purl.uniprot.org/citations/24671090http://purl.uniprot.org/core/author"Jacobson S.G."xsd:string
http://purl.uniprot.org/citations/24671090http://purl.uniprot.org/core/author"Tucker B.A."xsd:string
http://purl.uniprot.org/citations/24671090http://purl.uniprot.org/core/author"Huang W.C."xsd:string
http://purl.uniprot.org/citations/24671090http://purl.uniprot.org/core/author"Hauswirth W.W."xsd:string
http://purl.uniprot.org/citations/24671090http://purl.uniprot.org/core/author"Swaroop A."xsd:string
http://purl.uniprot.org/citations/24671090http://purl.uniprot.org/core/author"Ruan Q."xsd:string
http://purl.uniprot.org/citations/24671090http://purl.uniprot.org/core/author"Cideciyan A.V."xsd:string
http://purl.uniprot.org/citations/24671090http://purl.uniprot.org/core/author"Sumaroka A."xsd:string
http://purl.uniprot.org/citations/24671090http://purl.uniprot.org/core/author"Roman A.J."xsd:string
http://purl.uniprot.org/citations/24671090http://purl.uniprot.org/core/author"Boye S.L."xsd:string
http://purl.uniprot.org/citations/24671090http://purl.uniprot.org/core/author"Boye S.E."xsd:string
http://purl.uniprot.org/citations/24671090http://purl.uniprot.org/core/author"Ryals R.C."xsd:string
http://purl.uniprot.org/citations/24671090http://purl.uniprot.org/core/author"Olivares M.B."xsd:string
http://purl.uniprot.org/citations/24671090http://purl.uniprot.org/core/date"2014"xsd:gYear
http://purl.uniprot.org/citations/24671090http://purl.uniprot.org/core/name"PLoS One"xsd:string
http://purl.uniprot.org/citations/24671090http://purl.uniprot.org/core/pages"e92928"xsd:string
http://purl.uniprot.org/citations/24671090http://purl.uniprot.org/core/title"Natural history of cone disease in the murine model of Leber congenital amaurosis due to CEP290 mutation: determining the timing and expectation of therapy."xsd:string
http://purl.uniprot.org/citations/24671090http://purl.uniprot.org/core/volume"9"xsd:string
http://purl.uniprot.org/citations/24671090http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/24671090
http://purl.uniprot.org/citations/24671090http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/24671090
http://purl.uniprot.org/uniprot/#_E9Q9M0-mappedCitation-24671090http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/24671090
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